Tartrate salts of thiazollidnedione derivative

ABSTRACT

A novel pharmaceutical compound 5-[4-[2-(N-methyl-N-(2-pyridyl)amino) ethoxy]benzyl]thiazolidine-2,4-dione D(−) Tartrate or a solvate thereof, a process for preparing such a compound, a pharmaceutical composition comprising such a compound and the use of such a compound in medicine

[0001] This invention relates to a novel pharmaceutical, to a processfor the preparation of the pharmaceutical and to the use of thepharmaceutical in medicine.

[0002] European Patent Application, Publication Number 0,306,228 relatesto certain thiazolidinedione derivatives disclosed as havinghypoglycaemic and hypolipidaemic activity. The compound of example 30 ofEP 0,306,228 is5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione(hereinafter also referred to as “Compound (I)”).

[0003] International Patent Application, Publication Number WO94/05659discloses certain salts of the compounds of EP 0,306,228 one of which isthe tartrate salt. The preferred salt of WO94/05659 is the maleic acidsalt.

[0004] It has now been discovered that Compound (1) forms a noveltartrate salt (hereinafter also referred to as the “D(−) Tartrate”) thatis particularly stable and hence is suitable for bulk preparation andhandling. The D(−) Tartrate also has a high melting point and possessesgood bulk flow properties The D(−) Tartrate is therefore surprisinglyamenable to large scale pharmaceutical processing and especially tolarge scale milling.

[0005] The novel form can be prepared by an efficient, economic andreproducible process particularly suited to large-scale preparation.

[0006] The novel D(−) Tartrate also has useful pharmaceutical propertiesand in particular it is indicated to be useful for the treatment and/orprophylaxis of diabetes mellitus, conditions associated with diabetesmellitus and certain complications thereof.

[0007] Accordingly, the present invention provides5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione,D(−) tartrate salt or a solvate thereof.

[0008] Suitably, the D(−) Tartrate is a mono-tartrate salt Mono tartratesalts also optionally comprise another monovalent salting ion such as analkali metal or ammonium cation.

[0009] In one favoured aspect, the D(−) Tartrate provides an infraredspectrum substantially in accordance with FIG. 1.

[0010] In one favoured aspect, the D(−) Tartrate provides a Ramanspectrum substantially in accordance with FIG. 2

[0011] In one favoured aspect, the D(−) Tartrate provides an X-Raypowder diffraction pattern (XRPD) substantially in accordance with Table1 or FIG. 3.

[0012] In one favoured aspect, the D(−) Tartrate provides a Solid State¹³C NMR spectrum substantially in accordance with FIG. 4.

[0013] In one favoured aspect, the D(−) Tartrate provides a meltingpoint in the range of from 180 to 185° C., such as 180 to 183° C., forexample 181.6° C.

[0014] In a preferred aspect, the invention provides5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione,D(−) Tartrate salt, characterised in that it provides:

[0015] (i) an infrared spectrum substantially in accordance with FIG. 1;and

[0016] (ii) a Raman spectrum substantially in accordance with FIG. 2;and

[0017] (iii) an X-Ray powder diffraction pattern (XRPD) substantially inaccordance with Table 1 or FIG. 3; and

[0018] (iv) a Solid State ¹³C NMR spectrum substantially in accordancewith FIG. 4.

[0019] The present invention encompasses the D(−) Tartrate or solvatethereof isolated in pure form or when admixed with other materials. Thusin one aspect there is provided the D(−) Tartrate or solvate thereof inisolated form.

[0020] In a further aspect there is provided the D(−) Tartrate orsolvate thereof in a purified form.

[0021] In yet a further aspect there is provided the D(−) Tartrate orsolvate thereof in crystalline form.

[0022] Also, the invention provides the D(−) Tartrate or solvate thereofin a solid pharmaceutically acceptable form, such as a solid dosageform, especially when adapted for oral administration.

[0023] Moreover, the invention also provides the D(−) Tartrate orsolvate thereof in a pharmaceutically acceptable form, especially inbulk form, such form being particularly capable of being milled.

[0024] Furthermore, the invention provides the D(−) Tartrate or solvatethereof in a pharmaceutically acceptable form, especially in bulk form,such form having good flow properties, especially good bulk flowproperties.

[0025] A suitable solvate is a hydrate.

[0026] The invention also provides a process for preparing the D(−)Tartrate or a solvate thereof, characterised in that5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione(Compound (I)), or a salt thereof, preferably dispersed or dissolved ina suitable solvent, is reacted with a source of D(−) tartrate ion andthereafter, if required, a solvate of the resulting D(−) Tartrate isprepared; and the D(−) Tartrate or a solvate thereof is recovered.

[0027] A suitable reaction solvent is an alkanol, for examplepropan-2-ol or ethanol, or a hydrocarbon, such as toluene, a ketone,such as acetone, an ester, such as ethyl acetate, an ether such astetrahydrofuran, a nitrile such as acetonitrile, or a halogenatedhydrocarbon such as dichloromethane or water, or an organic acid such asacetic acid; or a mixture thereof.

[0028] Conveniently, the source of D(−) tartrate ion is D(−) tartaricacid. The D(−) tartaric acid is preferably added as a solid or insolution, for example in water or a lower alcohol such as methanol,ethanol, or propan-2-ol, or a mixture of solvents. An alternative sourceof D(−) tartrate ion is provided by a suitably soluble base salt of D(−)tartaric acid for example ammonium D(−) tartrate, or the D(−) tartaricacid salt of an amine, for example ethylamine or diethylamine.

[0029] The concentration of Compound (1) is preferably in the range 2 to25% weight/volume, more preferably in the range 5 to 20%. Theconcentration of D(−) tartaric acid solutions are preferably in therange of 5 to 130% weight/volume.

[0030] The reaction is usually carried out at ambient temperature or atan elevated temperature, for example at the reflux temperature of thesolvent, although any convenient temperature that provides the requiredproduct may be employed.

[0031] Solvates, such as hydrates, of the D(−) Tartrate are preparedaccording to conventional procedures.

[0032] Recovery of the required compound generally comprisescrystallisation from an appropriate solvent or mixture of solvents,conveniently the reaction solvent, usually assisted by cooling. Forexample, the D(−) tartrate may be crystallised from an alcohol such aspropan-2-ol or ethanol. An improved yield of the salt may be obtained byevaporation of some or all of the solvent or by crystallisation atelevated temperature followed by controlled cooling, optionally instages. Careful control of precipitation temperature may be used toimprove the reproducability of the product form.

[0033] Crystallisation can also be initiated by seeding with crystals ofthe D(−) Tartrate or a solvate thereof but this is not essential.

[0034] When the mono tartrate salt comprise another monovalent saltingion such as an alkali metal or ammonium cation the said ion isconveniently formed by reacting the mono tartrate salt with a solutionof the chosen monovalent salting ion for example a metal or ammoniumion. Alternatively Compound(I) may be treated with a mono tartrate saltof the said monovalent salting ion.

[0035] Compound (I) is prepared according to known procedures, such asthose disclosed in EP 0,306,228 and WO94/05659. The disclosures of EP0,306,228 and WO94/05659 are incorporated herein by reference.

[0036] D(−) tartaric acid is a commercially available compound.

[0037] When used herein the term “T_(onset)” is generally determined byDifferential Scanning Calorimetry and has a meaning generally understoodin the art, as for example expressed in Pharmaceutical Thermal Analysis,Techniques and Applications”, Ford and Timmins, 1989 as “The temperaturecorresponding to the intersection of the pre-transition baseline withthe extrapolated leading edge of the transition”.

[0038] When used herein in respect of certain compounds the term “goodflow properties” is suitably characterised by the said compound having aHausner ratio of less than or equal to 1.5, especially of less than orequal to 1.25.

[0039] “Hausner ratio” is an art accepted term.

[0040] When used herein the term ‘prophylaxis of conditions associatedwith diabetes mellitus’ includes the treatment of conditions such asinsulin resistance, impaired glucose tolerance, hyperinsulinaemia andgestational diabetes.

[0041] Diabetes mellitus preferably means Type II diabetes mellitus.

[0042] Conditions associated with diabetes include hyperglycaemia andinsulin resistance and obesity. Further conditions associated withdiabetes include hypertension, cardiovascular disease, especiallyatherosclerosis, certain eating disorders, in particular the regulationof appetite and food intake in subjects suffering from disordersassociated with under-eating, such as anorexia nervosa, and disordersassociated with over-eating, such as obesity and anorexia bulimiaAdditional conditions associated with diabetes include polycysticovarian syndrome and steroid induced insulin resistance.

[0043] The complications of conditions associated with diabetes mellitusencompassed herein includes renal disease, especially renal diseaseassociated with the development of Type II diabetes including diabeticnephropathy, glomerulonephritis, glomerular sclerosis, nephroticsyndrome, hypertensive nephrosclerosis and end stage renal disease.

[0044] As mentioned above the compound of the invention has usefultherapeutic properties: The present invention accordingly provides theD(−) Tartrate or a solvate thereof for use as an active therapeuticsubstance.

[0045] More particularly, the present invention provides the D(−)Tartrate or a solvate thereof for use in the treatment and/orprophylaxis of diabetes mellitus, conditions associated with diabetesmellitus and certain complications thereof.

[0046] The D(−) Tartrate or a solvate thereof may be administered per seor, preferably, as a pharmaceutical composition also comprising apharmaceutically acceptable carrier. Suitable methods for formulatingthe D(−) Tartrate or a solvate thereof are generally those disclosed forCompound (I) in the above mentioned publications.

[0047] Accordingly, the present invention also provides a pharmaceuticalcomposition comprising the D(−) Tartrate or a solvate thereof and apharmaceutically acceptable carrier therefor.

[0048] The D(−) Tartrate or a solvate thereof is normally administeredin unit dosage form.

[0049] The active compound may be administered by any suitable route butusually by the oral or parenteral routes. For such use, the compoundwill normally be employed in the form of a pharmaceutical composition inassociation with a pharmaceutical carrier, diluent and/or excipient,although the exact form of the composition will naturally depend on themode of administration.

[0050] Compositions are prepared by admixture and are suitably adaptedfor oral, parenteral or topical administration, and as such may be inthe form of tablets, capsules, oral liquid preparations, powders,granules, lozenges, pastilles, reconstitutable powders, injectable andinfusable solutions or suspensions, suppositories and transdermaldevices. Orally administrable compositions are preferred, in particularshaped oral compositions, since they are more convenient for generaluse.

[0051] Tablets and capsules for oral administration are usuallypresented in a unit dose, and contain conventional excipients such asbinding agents, fillers, diluents, tabletting agents, lubricants,disintegrants, colourants, flavourings, and wetting agents. The tabletsmay be coated according to well known methods in the art.

[0052] Suitable fillers for use include cellulose, mannitol, lactose andother similar agents. Suitable disintegrants include starch,polyvinylpyrrolidone and starch derivatives such as sodium starchglycollate. Suitable lubricants include, for example, magnesiumstearate. Suitable pharmaceutically acceptable wetting agents includesodium lauryl sulphate.

[0053] Solid oral compositions may be prepared by conventional methodsof blending, filling, tabletting or the like. Repeated blendingoperations may be used to distribute the active agent throughout thosecompositions employing large quantities of fillers. Such operations are,of course, conventional in the art.

[0054] Oral liquid preparations may be in the form of, for example,aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs,or may be presented as a dry product for reconstitution with water orother suitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example sorbitol,syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats,emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample, almond oil, fractionated coconut oil, oily esters such asesters of glycerine, propylene glycol, or ethyl alcohol; preservatives,for example methyl or propyl p-hydroxybenzoate or sorbic acid, and ifdesired conventional flavouring or colouring agents.

[0055] For parenteral administration, fluid unit dose forms are preparedcontaining a compound of the present invention and a sterile vehicle.The compound, depending on the vehicle and the concentration, can beeither suspended or dissolved. Parenteral solutions are normallyprepared by dissolving the active compound in a vehicle and filtersterilising before filling into a suitable vial or ampoule and sealing.Advantageously, adjuvants such as a local anaesthetic, preservatives andbuffering agents are also dissolved in the vehicle. To enhance thestability, the composition can be frozen after filling into the vial andthe water removed under vacuum.

[0056] Parenteral suspensions are prepared in substantially the samemanner except that the active compound is suspended in the vehicleinstead of being dissolved and sterilised by exposure to ethylene oxidebefore suspending in the sterile vehicle. Advantageously, a surfactantor wetting agent is included in the composition to facilitate uniformdistribution of the active compound.

[0057] As is common practice, the compositions will usually beaccompanied by written or printed directions for use in the medicaltreatment concerned.

[0058] As used herein the term ‘pharmaceutically acceptable’ embracescompounds, compositions and ingredients for both human and veterinaryuse: for example the term ‘pharmaceutically acceptable salt’ embraces aveterinarily acceptable salt.

[0059] The present invention further provides a method for the treatmentand/or prophylaxis of diabetes mellitus, conditions associated withdiabetes mellitus and certain complications thereof, in a human ornon-human mammal which comprises administering an effective, non-toxic,amount of D(−) Tartrate or a solvate thereof to a human or non-humanmammal in need thereof.

[0060] Conveniently, the active ingredient may be administered as apharmaceutical composition hereinbefore defined, and this forms aparticular aspect of the present invention.

[0061] In a further aspect the present invention provides the use ofD(−) Tartrate or a solvate thereof for the manufacture of a medicamentfor the treatment and/or prophylaxis of diabetes mellitus, conditionsassociated with diabetes mellitus and certain complications thereof.

[0062] In the treatment and/or prophylaxis of diabetes mellitus,conditions associated with diabetes mellitus and certain complicationsthereof the D(−) Tartrate or a solvate thereof may be taken in amountsso as to provide Compound (I) in suitable doses, such as those disclosedin EP 0,306,228, WO94/05659 or WO98/55122.

[0063] No adverse toxicological effects are indicated in the abovementioned treatments for the compounds of the invention.

[0064] The following examples illustrate the invention but do not limitit in any way.

EXAMPLES Example 15-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4dioneD-(−)-tartrate

[0065] A mixture of5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione(2.0 g), D-(−)-tartaric acid (0.84 g), acetone (90 ml) and deionisedwater (5 ml) was stirred and heated to 70° C. to give a clear solution.The reaction mixture was then cooled to 21° C., and the solvent wasremoved under reduced pressure. Toluene (50 ml) was added and themixture stirred and the solvent evaporated under reduced pressure. Ethylacetate (50 ml) and denatured ethanol (20 ml) were added to the residueand the mixture stirred and heated to reflux and then cooled to 21° C.The product was collected by filtration and dried under vacuum to give5-[[2-N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dioneD(−)-tartrate as a white crystalline solid (1.2 g).

[0066]¹H NMR (d⁶-DMSO): consistent with5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dioneD(−)-tartrate.

Example 25-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dioneD-(−)-tartrate

[0067] A mixture of5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione(4.5 g) and denatured ethanol (120 ml) was heated to reflux to give aclear solution. The solution was cooled to 70° C. and D-(−)-tartaricacid (1.9 g) was added and the stirred mixture heated to reflux. Thesolution was cooled to 45° C., seeded with crystals of5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dioneD(−) tartrate and sonicated for 5 minutes to give a white suspension.The mixture was cooled to 21° C. and the product collected byfiltration, washed with denatured ethanol (20 ml) and dried under vacuumfor 3 hours to give5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dioneD-(−)-tartrate as a white crystalline solid (5.8 g).

Example 35-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dioneD-(−)-tartrate

[0068] A mixture of5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione(5.0 g) and propan-2-ol (100 ml) was stirred and heated to reflux untila clear solution was observed. A solution of D-(−)-tartaric acid (2.1 g)in propan-2-ol (30 ml), at 60-70° C., was added to the reaction mixturewhich was then stirred at reflux for 5 minutes. The mixture was thencooled to 21° C. over a period of 90 minutes. The product was collectedby filtration, washed with propan-2-ol (50 ml) and dried under vacuum toprovide5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dioneD(−)-tartrate (6.7 g) as a white crystalline solid.

Example 45-[4-[2-(N-Methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione,D-(−)-tartrate

[0069] A solution of D-(−)-tartaric acid (8.4 g) in propan-2-ol (70 ml)was added to a stirred suspension of5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione(20.0 g) in propan-2-ol (400 ml) at reflux. The reaction mixture wasstirred at reflux until a clear solution was observed, then cooled to21° C. The white solid was collected by filtration, washed withpropan-2-ol (100 ml) then dried under vacuum for 2 hours at 21° C. toprovide5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dioneD-(−)-tartrate (26.9 g) as a white crystalline solid.

[0070] Characterising Data Recorded for the Product of Example 1:

[0071] The infrared absorption spectrum of a mineral oil dispersion ofthe product was obtained using a Nicolet 710 FT-IR spectrometer at 2cm⁻¹ resolution (FIG. 1). Data were digitised at 1 cm⁻¹ intervals. Bandswere observed at:

[0072] 3385, 2792, 1751, 1700, 1646, 1621, 1545, 1512, 1466, 1416, 1377,1357, 1304, 1267, 1233, 1217, 1168, 1153, 1076, 1060, 1033; 999, 927,901, 835, 773, 752, 716, 688, 618, 603, 589, 556, 527, 507 cm⁻¹.

[0073] The infrared spectrum of the solid product was recorded usingPerkin-Elmer Spectrum One FT-IR spectrometer fitted with a universal ATRaccessory. Bands were observed at:

[0074] 3384, 2937, 2787, 1751, 1694, 1645, 1620, 1609, 1543, 1511, 1466,1415, 1384, 1357, 1303, 1267, 1232, 1217, 1167, 1153, 1141, 1075, 1059,1032, 998, 927, 899, 832, 772, 751, 715, 686, 658 cm⁻¹.

[0075] The Raman spectrum of the product (FIG. 2) was recorded with thesample in an NMR tube using a Nicolet 960 E.S.P. FT-Raman spectrometer,at 4 cm⁻¹ resolution with excitation from a Nd:V04 laser (1064 nm) witha power output of 400 mW. Bands were observed at: 3101, 3065, 3043,2920, 1748, 1700, 1610, 1584, 1545, 1471, 1439, 1390, 1358, 1320, 1293,1236, 1207, 1177, 1146, 1060, 1035, 982, 930, 901, 828, 774, 741, 659,638, 621, 604, 507, 468, 431, 397, 349, 281, 99.8 cm⁻¹.

[0076] The X-Ray Powder Diffractogram pattern of the product (FIG. 3)was recorded using the following acquisition conditions: Tube anode: Cu,Generator tension: 40 kV, Generator current: 40 mA, Start angle: 2.0°2θ,End angle: 35.0°2θ, Step size: 0.02°2θ, Time per step: 2.5 seconds.Characteristic XRPD angles and relative intensities are recorded inTable 1. Angle Rel. Intensity 2θ° °/ 6.4 10.2 7.9 11.6 9.7 3.6 10.6 4.312.2 11.9 12.8 10.4 13.1 7.9 14.1 7.3 14.7 4.9 15.8 22.9 16.5 100 17.529.7 17.9 11 18.2 13.4 18.6 36 19.4 29.3 21.3 21.4 21.6 24.3 22.6 75.923.7 15.8 24.3 49 25.2 34 25.7 43 26.4 14.3 27.2 28.6 27.4 22.3 28.315.1 29.2 29.6 29.6 8.7 30.4 9.4 30.7 14.3 31.1 14.9 31.6 13.6 32.1 12.433.3. 15.2 33.8 16.6

[0077] The solid-state NMR spectrum of the product (FIG. 4) was recordedon a Bruker AMX360 instrument operating at 90.55 MHz: The solid waspacked into a 4 mm zirconia MAS rotor fitted with a Kel-F cap and rotorspun at ca. 10 kHz. The ¹³C MAS spectrum was acquired bycross-polarisation from Hartmann-Hahn matched protons (CP contact time 3ms, repetition time 15 s) and protons were decoupled during acquisitionusing a two-pulse phase modulated (TPPM) composite sequence. Chemicalshifts were externally referenced to the carboxylate signal of glycineat 176.4 ppm relative to TMS and were observed at:

[0078] 181.2, 179.0, 177.4, 174.7, 173.0, 158.2, 156.9, 150.3, 145.6,144.7, 141.9, 139.3, 136.1, 131.7, 126.6, 118.1, 113.7, 111.0, 110.0,75.2, 74.6, 73.7, 73.0, 64.6, 56.6, 55.7, 50.8, 47.4, 40.6, 38.8, 36.7,34.8 ppm.

[0079] Properties of the D(−) Tartrate, Recorded for the Product ofExample 4

[0080] Solid State Stability of the D(−) Tartrate

[0081] The solid state stability of the drug substance was determined bystoring approximately 1.0 g of the material in a glass bottle at i) 40°C./75% Relative Humidity (RH), open exposure, for 1 month and b) at 50°C., closed, for 1 month. The material was assayed by HPLC for finalcontent and degradation products in both cases.

[0082] a) 40° C./75% RH: No significant degradation observed (HPLC assay96% initial).

[0083] b) 50° C.: No significant degradation observed (HPLC assay 98%initial).

[0084] Flow Properties of the D(−) Tartrate:

[0085] The ratio between the bulk density and the tapped bulk density(Hausner Ratio) of the D(−) Tartrate was determined using standardmethods (“Pharmaceutics—The Science of Dosage Form Design”, editor M.Aulton, 1988, published by: Churchill Livingstone).

[0086] Hausner Ratio: 1.2

[0087] Melting Point of the D(−) Tartrate

[0088] The melting point of the D(−) Tartrate was determined accordingto the method described in the U.S. Pharmacopoeia, USP 23, 1995, <741>“Melting range or temperature, Procedure for Class Ia”, using a Buchi545 melting point instrument.

[0089] Melting Point: 181.6° C.

[0090] T_(onset) of the D(−) Tartrate

[0091] The T_(onset) of the drug substance was determined byDifferential Scanning Calorimetry using a Perkin-Elmer DSC7 apparatus.

[0092] T_(onset) (10° C./minute, closed pan): 187° C.

1. A compound5-[4-[2-N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione,D(−) tartrate salt or a solvate thereof.
 2. A compound according toclaim 1, characterised in that it provides: (i) an infrared spectrumsubstantially in accordance with FIG. 1; (ii) a Raman spectrumsubstantially in accordance with FIG. 2; (iii) an X-Ray powderdiffraction pattern (XRPD) substantially in accordance with Table 1 orFIG. 3; or (iv) a Solid State ¹³C NMR spectrum substantially inaccordance with FIG.
 4. 3. A compound according to claim 1,characterised in that it provides two or more of: (i) an infraredspectrum substantially in accordance with FIG. 1; and (ii) a Ramanspectrum substantially in accordance with FIG. 2; and (iii) an X-Raypowder diffraction pattern (XRPD) substantially in accordance with Table1 or FIG. 3; and (iv) a Solid State ¹³C NMR spectrum substantially inaccordance with FIG.
 4. 4. A compound according to any one of claims 1to 3, in purified form.
 5. A compound according to any one of claims 1to 3, in a solid dosage form.
 6. A compound according to any one ofclaims 1 to 3, in a pharmaceutically acceptable form capable of beingmilled.
 7. A compound according to any one of claims 1 to 3, in apharmaceutically acceptable form having good flow properties.
 8. Aprocess for preparing the D(−) Tartrate or a solvate thereof,characterised in that characterised in that5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione(Compound (I)), or a salt thereof, is reacted with a source of D(−)tartrate ion and thereafter, if required, a solvate of the resultingD(−) Tartrate is prepared; and the D(−) Tartrate or a solvate thereof isrecovered.
 9. A pharmaceutical composition comprising5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dioneD(−) tartrate or a solvate thereof. and a pharmaceutically acceptablecarrier therefor.
 10. A compound5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dioneD(−) tartrate or a solvate thereof for use as an active therapeuticsubstance.
 11. A use of5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dioneD(−) tartrate or a solvate thereof, for the manufacture of a medicamentfor the treatment and/or prophylaxis of diabetes mellitus, conditionsassociated with diabetes mellitus and certain complications thereof.